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Competing Interests: We declare no competing interests and no funding was obtained for this Comment. We thank Jochen Cals for his helpful input.

Introduction: Acute febrile illness (AFI), traditionally attributed to malaria, is a common reason for seeking primary healthcare in rural South and Southeast Asia. However, malaria transmission has declined while health workers are often poorly equipped to manage non-malarial AFIs. This results in indiscriminate antibiotic prescribing and care escalation, which promotes antibiotic resistance and may increase healthcare costs. To address this problem, an electronic clinical decision support algorithm (eCDSA) called 'Electronic clinical Decision support for Acute fever Management (EDAM)' has been developed for primary health workers which integrates clinical, epidemiological and vital sign data with simple point-of-care tests to produce a diagnosis and management plan., Methods and Analysis: This is a pragmatic cluster-randomised trial aiming to assess the effect of EDAM and related training on antibiotic prescribing rates in rural Cambodian primary health centres (PHCs) as the primary outcome, along with a range of secondary outcomes including safety. Patients with AFI are eligible for recruitment if they are aged ≥1 year. A cluster is defined as a PHC and PHCs will be randomised to control (standard of care) and intervention (EDAM and associated training) arms, with 15 PHCs per arm. Patients will be followed up after 7 days to ascertain the safety profile of EDAM. Each PHC will recruit 152 patients (total 4560), based on a baseline antibiotic prescription rate of 25% and expected reduction to 17.5% with EDAM., Ethics and Dissemination: Results will be published in international peer-reviewed journals to inform the design of future versions of EDAM and of future trials of similar eCDSAs and other digital health interventions targeted towards rural populations. This study was approved by the Oxford University Tropical Research Ethics Committee (550-23) and the Cambodian National Ethics Committee for Health Research (395-NECHR)., Trial Registration Number: International Standard Randomized Controlled Trial Number Registry (ISRCTN15157105)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Southeast Asia is undergoing an epidemiological transition with non-communicable illnesses becoming increasingly important, yet infectious diseases (tuberculosis, HIV, hepatitis B, malaria) remain widely prevalent in some populations, while emerging and zoonotic diseases threaten. There are also limited population-level estimates of many important heath conditions. This restricts evidence-based decision-making for disease control and prevention priorities. Cross-sectional surveys can be efficient epidemiological tools to measure the prevalence of a wide range of diseases, but no systematic assessment of their coverage of different health conditions has been produced for the region., Methods: We conducted a systematic search in Medline, Embase, Global Health, CINAHL, Scopus, Web of Science Core Collection, and Global Index Medicus, and additionally Google Scholar. Our inclusion criteria were cross-sectional surveys conducted with community-based recruitment, in Bangladesh, Cambodia, Laos, Myanmar, and Thailand, published between January 1, 2010 and January 27, 2021, and reporting the prevalence of any health condition., Results: 542 publications from 337 surveys were included. Non-communicable conditions (n = 205) were reported by more surveys than infectious conditions (n = 124). Disability (n = 49), self-report history of any disease or symptoms (n = 35), and self-perceived health status (n = 34), which reflect a holistic picture of health, were studied by many fewer surveys. In addition, 45 surveys studied symptomatic conditions which overlap between non-communicable and infectious conditions. The most surveyed conditions were undernutrition, obesity, hypertension, diabetes, intestinal parasites, malaria, anemia, diarrhea, fever, and acute respiratory infections. These conditions overlap with the most important causes of death and disability in the Global Burden of Disease study. However, other high-burden conditions (e.g. hearing loss, headache disorder, low back pain, chronic liver and kidney diseases, and cancers) were rarely studied., Conclusion: There were relatively few recent surveys from which to estimate representative prevalences and trends of health conditions beyond those known to be high burden. Expanding the spectrum of health conditions in cross-sectional surveys could improve understanding of evolving disease patterns in the region., (© 2024. The Author(s).)

Introduction: In low-income and middle-income countries in Southeast Asia, the burden of diseases among rural population remains poorly understood, posing a challenge for effective healthcare prioritisation and resource allocation. Addressing this knowledge gap, the South and Southeast Asia Community-based Trials Network (SEACTN) will undertake a survey that aims to determine the prevalence of a wide range of non-communicable and communicable diseases, as one of the key initiatives of its first project-the Rural Febrile Illness project (RFI). This survey, alongside other RFI studies that explore fever aetiology, leading causes of mortality, and establishing village and health facility maps and profiles, will provide an updated epidemiological background of the rural areas where the network is operational., Methods and Analysis: During 2022-2023, a cross-sectional household survey will be conducted across three SEACTN sites in Bangladesh, Cambodia and Thailand. Using a two-stage cluster-sampling approach, we will employ a probability-proportional-to-size sample method for village, and a simple random sample for household, selection, enrolling all members from the selected households. Approximately 1500 participants will be enrolled per country. Participants will undergo questionnaire interview, physical examination and haemoglobin point-of-care testing. Blood samples will be collected and sent to central laboratories to test for chronic and acute infections, and biomarkers associated with cardiovascular disease, and diabetes. Prevalences will be presented as an overall estimate by country, and stratified and compared across sites and participants' sociodemographic characteristics. Associations between disease status, risk factors and other characteristics will be explored., Ethics and Dissemination: This study protocol has been approved by the Oxford Tropical Research Ethics Committee, National Research Ethics Committee of Bangladesh Medical Research Council, the Cambodian National Ethics Committee for Health Research, the Chiang Rai Provincial Public Health Research Ethical Committee. The results will be disseminated via the local health authorities and partners, peer-reviewed journals and conference presentations., Trial Registration Number: NCT05389540., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Multiplex lateral flow rapid diagnostic tests (LF-RDTs) may aid management of patients with acute non-malarial febrile illness (NMFI) in rural south and southeast Asia. We aimed to evaluate the cost-effectiveness in Cambodia and Bangladesh of a putative, as-yet-undeveloped LF-RDT capable of diagnosing enteric fever and dengue, as well as measuring C-reactive protein (CRP) to guide antibiotic prescription, in primary care patients with acute NMFI., Methods: A country-specific decision tree model-based cost-effectiveness analysis was conducted from a health system plus limited societal perspective considering the cost of antimicrobial resistance. Parameters were based on data from a large observational study on the regional epidemiology of acute febrile illness, published studies, and procurement price lists. Costs were expressed in US$ (value in 2022), and cost-effectiveness evaluated by comparing incremental cost-effectiveness ratios with conservative opportunity cost-based willingness-to-pay thresholds and the more widely used threshold of per capita gross domestic product (GDP)., Findings: Compared to standard of care, LF-RDT-augmented clinical assessment was dominant in Cambodia, being more effective and cost-saving. The cost per disability-adjusted life year (DALY) averted in Bangladesh was US$482, slightly above the conservative opportunity cost-based willingness-to-pay threshold of US$388 and considerably lower than the GDP-based threshold of US$2687. The intervention remained dominant in Cambodia and well below the GDP-based threshold in Bangladesh when antimicrobial resistance costs were disregarded., Interpretation: These findings provide guidance for academic, industry, and policymaker stakeholders involved in acute NMFI diagnostics. While definitive conclusions cannot be made in the absence of established thresholds, our results suggest that similar results are highly likely in some target settings and possible in others., Funding: Wellcome Trust, UK Government, Royal Australasian College of Physicians, and Rotary Foundation., Competing Interests: This research was funded in whole, or in part, by the Wellcome Trust [215604/Z/19/Z]. RC was also funded by the UK Government through a Commonwealth Scholarship, the Royal Australasian College of Physicians through the Bushell Travelling Fellowship in Medicine or the Allied Sciences, and the Rotary Foundation through a Global Grant Scholarship. For open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The authors declare no competing interests., (© 2024 The Author(s).)

Background: Community-based health programmes have been a cornerstone of primary care in Laos for decades. The study presented here aimed to document prospects for the development of current programmes, considering perceptions about health and health care priorities in the communities, implementation challenges, the policy landscape and opportunities associated with the availability of new technologies., Methods: The research design primarily involved qualitative in-depth interviews with stakeholders (n = 35) responsible for the planning, management, or implementation of community-based care in Laos at different levels of the health system. These included health managers at central departments or institutes of the Ministry of Health, provincial health departments, district health offices, heads of health centres, village health volunteers, community representatives, and international stakeholders., Results: There was consensus that service delivery is still a challenge in many areas, due to geographic inaccessibility of health facilities, communication barriers, health-seeking behaviour, trust, and gender discrimination, particularly among ethnic minorities. In these settings, community health workers have the potential to extend the reach of the formal health system, acting as cultural brokers across sectors of society, ethnicities, and worldviews. To maximise impact, planners need to carefully consider the implementation model, financing arrangements, health system integration, and changing health priorities in the communities., Conclusions: This study examined challenges to, and opportunities for, the expansion and health system integration of community-based care in Laos. Further development and horizontal integration of community-based care remains a complex financing and governance challenge, although the renewed emphasis on primary care and the ongoing process of decentralisation provide a favourable policy environment in the country to sustain and potentially expand existing programmes., (© 2024. The Author(s).)

In Southeast Asia malaria elimination is targeted by 2030. Cambodia aims to achieve this by 2025, driven in large part by the urgent need to control the spread of artemisinin-resistant falciparum malaria infections. Rapid elimination depends on sustaining early access to diagnosis and effective treatment. In much of Cambodia, rapid elimination will rely on a village malaria worker (VMW) network. Yet as malaria declines and is no longer a common cause of febrile illness, VMWs may become less popular with febrile patients, as VMWs do not diagnose or treat other conditions at present. There is a risk that VMWs become inactive and malaria rebounds before the complete interruption of transmission is achieved.During 2021-23 a large-scale operational research study was conducted in western Cambodia to explore how a VMW network could be sustained by including health activities that cover non-malarial illnesses to encourage febrile patients to continue to attend. 105 VMWs received new rapid diagnostic tests (including dengue antigen-antibody and combined malaria/C-reactive protein tests), were trained in electronic data collection, and attended health education packages on hygiene and sanitation, disease surveillance and first aid, management of mild illness, and vaccination and antenatal care.In August 2023 the National Malaria Control Programme of Cambodia convened a stakeholder meeting in Battambang, Cambodia. Findings from the study were reviewed in the context of current malaria elimination strategies. The discussions informed policy options to sustain the relevance of the VMW network in Cambodia, and the potential for its integration with other health worker networks. This expansion could ensure VMWs remain active and relevant until malaria elimination is accomplished., (© 2023. The Author(s).)

Introduction: Causes of deaths often go unrecorded in lower income countries, yet this information is critical. Verbal autopsy is a questionnaire interview with a family member or caregiver to elicit the symptoms and circumstances preceding a death and assign a probable cause. The social and cultural aspects of verbal autopsy have gotten less attention than the technical aspects and have not been widely explored in South and Southeast Asia settings., Methods: Between October 2021 and March 2023, prior to implementing a verbal autopsy study at rural sites in Bangladesh, Cambodia, Laos, Myanmar and Thailand, focus group discussions were conducted with village heads, religious leaders and community members from varied demographic backgrounds. Thematic analysis elucidated customs and traditional views surrounding death to understand local ethnocultural sensitivities., Results: We found that death rituals varied greatly among religions, ethnicities and by socioeconomic status. Mourning periods were reported to last 3-100 days and related to the cause of death, age and how close the deceased person was to the family. Participants advised that interviews should happen after mourning periods to avoid emotional distress, but not long after so as to avoid recall bias. Interviewers should be introduced to respondents by a trusted local person. To provide reassurance and confidentiality, a family's residence is the preferred interview location. Interview questions require careful local language translation, and community sensitisation is important before data collection., Conclusion: Verbal autopsy is acceptable across a wide range of cultural settings in Southeast Asia, provided that local norms are preidentified and followed., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Accurate and reliable guidelines for referral of children from resource-limited primary care settings are lacking. We identified three practicable paediatric severity scores (the Liverpool quick Sequential Organ Failure Assessment (LqSOFA), the quick Pediatric Logistic Organ Dysfunction-2, and the modified Systemic Inflammatory Response Syndrome) and externally validated their performance in young children presenting with acute respiratory infections (ARIs) to a primary care clinic located within a refugee camp on the Thailand-Myanmar border. This secondary analysis of data from a longitudinal birth cohort study consisted of 3010 ARI presentations in children aged ≤ 24 months. The primary outcome was receipt of supplemental oxygen. We externally validated the discrimination, calibration, and net-benefit of the scores, and quantified gains in performance that might be expected if they were deployed as simple clinical prediction models, and updated to include nutritional status and respiratory distress. 104/3,010 (3.5%) presentations met the primary outcome. The LqSOFA score demonstrated the best discrimination (AUC 0.84; 95% CI 0.79-0.89) and achieved a sensitivity and specificity > 0.80. Converting the scores into clinical prediction models improved performance, resulting in ~ 20% fewer unnecessary referrals and ~ 30-50% fewer children incorrectly managed in the community. The LqSOFA score is a promising triage tool for young children presenting with ARIs in resource-limited primary care settings. Where feasible, deploying the score as a simple clinical prediction model might enable more accurate and nuanced risk stratification, increasing applicability across a wider range of contexts., (© 2023. The Author(s).)

Background: The decline of malaria in Southeast Asia means other causes of fever are increasingly relevant, but often undiagnosed. The objective of this study was to assess the feasibility of point-of-care tests to diagnose acute febrile illnesses in primary care settings., Methods: A mixed-methods study was conducted at nine rural health centres in western Cambodia. Workshops introduced health workers to the STANDARD(TM) Q Dengue Duo, STANDARD(TM) Q Malaria/CRP Duo and a multiplex biosensor detecting antibodies and/or antigens of eight pathogens. Sixteen structured observation checklists assessed users' performances and nine focus group discussions explored their opinions., Results: All three point-of-care tests were performed well under assessment, but sample collection was difficult for the dengue test. Respondents expressed that the diagnostics were useful and could be integrated into routine clinical care, but were not as convenient to perform as standard malaria rapid tests. Health workers recommended that the most valued point-of-care tests would directly inform clinical management (e.g. a decision to refer a patient or to provide/withhold antibiotics)., Conclusions: Deployment of new point-of-care tests to health centres could be feasible and acceptable if they are user-friendly, selected for locally circulating pathogens and are accompanied by disease-specific education and simple management algorithms., (© The Author(s) 2023. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Background: Early access to correct diagnosis and appropriate treatment is essential for malaria elimination, and in Cambodia this relies on village malaria workers (VMWs). Decreasing malaria transmission leave VMWs with diminished roles. Activities related to the control of other health conditions could keep these community health workers relevant., Methods: During 2022, 120 VMWs attended training at local health centres on four health education packages: 1. hygiene and sanitation; 2. disease surveillance; 3. management of mild illness; 4. vaccination and antenatal care. All training and evaluation sessions were documented through meeting minutes, and 19 focus group discussions (FGDs) were conducted among VMWs and health centre personnel. Audio-records of FGDs were transcribed and translated in English and underwent thematic analysis., Results: VMWs reported strong interest in the training and welcomed the expansion of their roles thus assuring their continued relevance. VMWs prioritized disease surveillance and management of mild illness among the available training packages because these topics were seen as most relevant. While training was considered comprehensible and important, the low literacy among VMWs was an impediment suggesting training materials need to be delivered visually. Since VMWs have limited resources, incentives could ensure that VMWs are motivated to undertake additional roles and responsibilities., Conclusions: The transformation of VMWs into community health workers with roles beyond malaria is a promising approach for sustaining health care provision in remote areas. Training needs to consider the low scientific literacy, time constraints and limited resources of VMWs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Betrian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: In previous trials, point-of-care testing of C-reactive protein (CRP) concentrations safely reduced antibiotic use in non-severe acute respiratory infections in primary care. However, these trials were done in a research-oriented context with close support from research staff, which could have influenced prescribing practices. To better inform the potential for scaling up point-of-care testing of CRP in respiratory infections, we aimed to do a pragmatic trial of the intervention in a routine care setting., Methods: We did a pragmatic, cluster-randomised controlled trial at 48 commune health centres in Viet Nam between June 1, 2020, and May 12, 2021. Eligible centres served populations of more than 3000 people, handled 10-40 respiratory infections per week, had licensed prescribers on site, and maintained electronic patient databases. Centres were randomly allocated (1:1) to provide point-of-care CRP testing plus routine care or routine care only. Randomisation was stratified by district and by baseline prescription level (ie, the proportion of patients with suspected acute respiratory infections to whom antibiotics were prescribed in 2019). Eligible patients were aged 1-65 years and visiting the commune health centre for a suspected acute respiratory infection with at least one focal sign or symptom and symptoms lasting less than 7 days. The primary endpoint was the proportion of patients prescribed an antibiotic at first attendance in the intention-to-treat population. The per-protocol analysis included only people who underwent CRP testing. Secondary safety outcomes included time to resolution of symptoms and frequency of hospitalisation. This trial is registered with ClinicalTrials.gov, NCT03855215., Findings: 48 commune health centres were enrolled and randomly assigned, 24 to the intervention group (n=18 621 patients) and 24 to the control group (n=21 235). 17 345 (93·1%) patients in the intervention group were prescribed antibiotics, compared with 20 860 (98·2%) in the control group (adjusted relative risk 0·83 [95% CI 0·66-0·93]). Only 2606 (14%) of 18 621 patients in the intervention group underwent CRP testing and were included in the per-protocol analysis. When analyses were restricted to this population, larger reductions in prescribing were noted in the intervention group compared with the control group (adjusted relative risk 0·64 [95% CI 0·60-0·70]). Time to resolution of symptoms (hazard ratio 0·70 [95% CI 0·39-1·27]) and frequency of hospitalisation (nine in the intervention group vs 17 in the control group; adjusted relative risk 0·52 [95% CI 0·23-1·17]) did not differ between groups., Interpretation: Use of point-of-care CRP testing efficaciously reduced prescription of antibiotics in patients with non-severe acute respiratory infections in primary health care in Viet Nam without compromising patient recovery. The low uptake of CRP testing suggests that barriers to implementation and compliance need to be addressed before scale-up of the intervention., Funding: Australian Government, UK Government, and the Foundation for Innovative New Diagnostics., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The soluble urokinase plasminogen activator receptor (suPAR) has been proposed as a biomarker for risk stratification of patients presenting with acute infections. However, most studies evaluating suPAR have used platform-based assays, the accuracy of which may differ from point-of-care tests capable of informing timely triage in settings without established laboratory capacity. Using samples and data collected during a prospective cohort study of 425 patients presenting with moderate Covid-19 to two hospitals in India, we evaluated the analytical performance and prognostic accuracy of a commercially-available rapid diagnostic test (RDT) for suPAR, using an enzyme-linked immunosorbent assay (ELISA) as the reference standard. Our hypothesis was that the suPAR RDT might be useful for triage of patients presenting with moderate Covid-19 irrespective of its analytical performance when compared with the reference test. Although agreement between the two tests was limited (bias = -2.46 ng/mL [95% CI = -2.65 to -2.27 ng/mL]), prognostic accuracy to predict supplemental oxygen requirement was comparable, whether suPAR was used alone (area under the receiver operating characteristic curve [AUC] of RDT = 0.73 [95% CI = 0.68 to 0.79] vs. AUC of ELISA = 0.70 [95% CI = 0.63 to 0.76]; p = 0.12) or as part of a published multivariable prediction model (AUC of RDT-based model = 0.74 [95% CI = 0.66 to 0.83] vs. AUC of ELISA-based model = 0.72 [95% CI = 0.64 to 0.81]; p = 0.78). Lack of agreement between the RDT and ELISA in our cohort warrants further investigation and highlights the importance of assessing candidate point-of-care tests to ensure management algorithms reflect the assay that will ultimately be used to inform patient care. Availability of a quantitative point-of-care test for suPAR opens the door to suPAR-guided risk stratification of patients with Covid-19 and other acute infections in settings with limited laboratory capacity., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Sabine Dittrich and Jennifer Osborn declare that they are employed by FIND. All other authors have declared that no competing interests exist., (Copyright: © 2023 Chandna et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background : Antimicrobial resistance surveillance is essential for empiric antibiotic prescribing, infection prevention and control policies and to drive novel antibiotic discovery. However, most existing surveillance systems are isolate-based without supporting patient-based clinical data, and not widely implemented especially in low- and middle-income countries (LMICs). Methods : A Clinically-Oriented Antimicrobial Resistance Surveillance Network (ACORN) II is a large-scale multicentre protocol which builds on the WHO Global Antimicrobial Resistance and Use Surveillance System to estimate syndromic and pathogen outcomes along with associated health economic costs. ACORN-healthcare associated infection (ACORN-HAI) is an extension study which focuses on healthcare-associated bloodstream infections and ventilator-associated pneumonia. Our main aim is to implement an efficient clinically-oriented antimicrobial resistance surveillance system, which can be incorporated as part of routine workflow in hospitals in LMICs. These surveillance systems include hospitalised patients of any age with clinically compatible acute community-acquired or healthcare-associated bacterial infection syndromes, and who were prescribed parenteral antibiotics. Diagnostic stewardship activities will be implemented to optimise microbiology culture specimen collection practices. Basic patient characteristics, clinician diagnosis, empiric treatment, infection severity and risk factors for HAI are recorded on enrolment and during 28-day follow-up. An R Shiny application can be used offline and online for merging clinical and microbiology data, and generating collated reports to inform local antibiotic stewardship and infection control policies. Discussion : ACORN II is a comprehensive antimicrobial resistance surveillance activity which advocates pragmatic implementation and prioritises improving local diagnostic and antibiotic prescribing practices through patient-centred data collection. These data can be rapidly communicated to local physicians and infection prevention and control teams. Relative ease of data collection promotes sustainability and maximises participation and scalability. With ACORN-HAI as an example, ACORN II has the capacity to accommodate extensions to investigate further specific questions of interest., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Mo Y et al.)

Background: Fever is a common reason to seek healthcare in Southeast Asia, and the decline of malaria has complexified how is perceived, and what actions are taken towards it. We investigated the concept of fever and the determinants influencing health-seeking behaviours among migrants on the Thai-Myanmar border, where rapid economic development collides with precarious political and socio-economic conditions., Methods: We implemented a mixed-methods study between August to December 2019. Phase I used a qualitative approach, with in-depth interviews and focus group discussions. Phase II used a quantitative approach with a close-ended questionnaire based on Phase I findings. A conditional inference tree (CIT) model first identified geographic and socio-demographic determinants, which were then tested using a logistic regression model., Results: Fever corresponded to a high diversity of conceptions, symptoms and believed causes. Self-medication was the commonest behaviour at fever onset. If fever persisted, migrants primarily sought care in humanitarian cost-free clinics (45.5%, 92/202), followed by private clinics (43.1%, 87/202), health posts (36.1%, 73/202), public hospitals (33.7%, 68/202) and primary care units (30, 14.9%). The qualitative analysis identified distance and legal status as key barriers for accessing health care. The quantitative analysis further investigated determinants influencing health-seeking behaviour: living near a town where a cost-free clinic operated was inversely associated with seeking care at health posts (adjusted odds ratio [aOR], 0.40, 95% confidence interval [95% CI] [0.19-0.86]), and public hospital attendance (aOR 0.31, 95% CI [0.14-0.67]). Living further away from the nearest town was associated with health posts attendance (aOR 1.05, 95% CI [1.00-1.10] per 1 km). Having legal status was inversely associated with cost-free clinics attendance (aOR 0.27, 95% CI [0.10-0.71]), and positively associated with private clinic and public hospital attendance (aOR 2.56, 95% CI [1.00-6.54] and 5.15, 95% CI [1.80-14.71], respectively)., Conclusions: Fever conception and believed causes are context-specific and should be investigated prior to any intervention. Distance to care and legal status were key determinants influencing health-seeking behaviour. Current economic upheavals are accelerating the unregulated flow of undocumented migrants from Myanmar to Thailand, warranting further inclusiveness and investments in the public health system., (© 2023. The Author(s).)

Reliable tools to inform outpatient management of childhood pneumonia in resource-limited settings are needed. We investigated the value added by biomarkers of the host infection response to the performance of the Liverpool quick Sequential Organ Failure Assessment score (LqSOFA), for triage of children presenting with pneumonia to a primary care clinic in a refugee camp on the Thailand-Myanmar border. 900 consecutive presentations of children aged ≤ 24 months meeting WHO pneumonia criteria were included. The primary outcome was receipt of supplemental oxygen. We compared discrimination of a clinical risk score (LqSOFA) to markers of endothelial injury (Ang-1, Ang-2, sFlt-1), immune activation (CHI3L1, IP-10, IL-1ra, IL-6, IL-8, IL-10, sTNFR-1, sTREM-1), and inflammation (CRP, PCT), and quantified the net benefit of including biomarkers alongside LqSOFA. We evaluated the differential contribution of LqSOFA and host biomarkers to the diagnosis and prognosis of pneumonia severity. 49/900 (5.4%) presentations met the primary outcome. Discrimination of LqSOFA and Ang-2, the best performing biomarker, were comparable (AUC 0.82 [95% CI 0.76-0.88] and 0.81 [95% CI 0.74-0.87] respectively). Combining Ang-2 with LqSOFA improved discrimination (AUC 0.91; 95% CI 0.87-0.94; p < 0.001), and resulted in greater net benefit, with 10-30% fewer children who required oxygen supplementation incorrectly identified as safe for community-based management. Ang-2 had greater prognostic utility than LqSOFA to identify children requiring supplemental oxygen later in their illness course. Combining Ang-2 and LqSOFA could guide referrals of childhood pneumonia from resource-limited community settings. Further work on test development and integration into patient triage is required., (© 2023. The Author(s).)

C-reactive protein (CRP) point-of-care testing can reduce antibiotic prescribing in primary care patients with febrile and respiratory illness, yet little is known about its effects on treatment-seeking behavior. If patients go on to source antibiotics elsewhere, the impact of CRP testing will be limited. A randomized controlled trial assessed the impact of CRP testing on antibiotic prescriptions in Myanmar and Thai primary care patients with a febrile illness. Here we report patients' treatment-seeking behavior before and during the two-week study period. Self-reported antibiotic use is compared against urine antibacterial activity. Patients' opinions towards CRP testing were evaluated. Antibiotic use before study enrolment was reported by 5.4% while antimicrobial activity was detected in 20.8% of samples tested. During the study period, 14.8% of the patients sought additional healthcare, and 4.3% sourced their own antibiotics. Neither were affected by CRP testing. Overall, patients' satisfaction with their care and CRP testing was high. CRP testing did not affect patients' treatment-seeking behavior during the study period whilst modestly reducing antibiotic prescriptions. CRP testing appears to be acceptable to patients and their caregivers., Competing Interests: Conflict of interests: SD was employed by FIND the global alliance for diagnostics during the study period. The other authors declare no conflict of interest; all authors confirm accuracy.

Background: Compared with ice-based vaccine carriers (IBVCs), iceless vaccine carrier (ILVC) last-mile delivery could optimize vaccine effectiveness by reducing spoilage. We estimated ILVC-associated spoilage costs averted and cost effectiveness., Methods: IBVC vaccine spoilage costs were estimated for six vaccines. ILVC incremental costs were based on yearly ILVC cost over total doses. Cost effectiveness was estimated via Markov modeling of rotavirus vaccine., Results: The spoilage cost using IBVCs was US$9 603 294. Using ILVCs, the incremental cost per vaccine dose was US$0.026, the cost-benefit ratio was 0.28, the number of averted disability-adjusted life years was 0.03 per child and there was a saving of US$0.80 per child vaccinated., Conclusions: ILVCs may bring cost savings and health gains compared with IBVCs., (© The Author(s) 2022. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Background: Fever is a common presenting symptom in low- and middle-income countries (LMICs). It was previously assumed that malaria was the cause in such patients, but its incidence has declined rapidly. The urgent need to develop point-of-care tests for the most important causes of non-malarial acute febrile illness is hampered by the lack of robust epidemiological data. We sought to obtain expert consensus on analytes which should be prioritized for inclusion in fingerprick blood-based multiplex lateral flow rapid diagnostic tests (LF-RDTs) targeted towards four categories of patients with acute non-malarial fever in South and Southeast Asian LMICs, stratified by age (paediatric vs. adult) and care setting (primary vs. secondary care)., Methodology/principal Findings: We conducted a two-round modified e-Delphi survey. A total of 84 panellists were invited, consisting of seven each from 12 countries, divided into three regional panels (Mainland Southeast Asia, Maritime Southeast Asia, and South Asia). Panellists were asked to rank their top seven analytes for inclusion in LF-RDTs to be used in each patient category, justify their choices, and indicate whether such LF-RDTs should be incorporated into algorithm-based clinical decision support tools. Thirty-six panellists (43%) participated in the first round and 44 (52%) in the second. There was consensus that such LF-RDTs should be incorporated into clinical decision support tools. At a minimum, these LF-RDTs should be able to diagnose dengue and enteric fever in all patient categories. There was a clear preference to develop LF-RDTs for pathogens not readily detected by existing technologies, and for direct diagnosis through antigen detection. Pathogen biomarkers were prioritized over host inflammatory biomarkers, with CRP being the only one ranked consistently highly., Conclusions/significance: Our results provide guidance on prioritizing analytes for inclusion in context-specific multiplex LF-RDTs and similar platforms for non-malarial acute febrile illness, for which there is an urgent unmet need., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Chew et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: This study aims to investigate patterns of antibiotic prescribing and to determine patient-specific factors associated with the choice of antibiotics by the World Health Organization's Access-Watch-Reserve (WHO AWaRe) class for acute respiratory infections (ARIs) in rural primary care settings in northern Vietnam., Methods: We retrospectively reviewed health records for outpatients who were registered with the Vietnamese Health Insurance Scheme, visited one of 112 commune health centres in 6 rural districts of Nam Dinh province, Vietnam during 2019, and were diagnosed with ARIs. Patient-level prescription data were collected from the electronic patient databases. We used descriptive statistics to investigate patterns of antibiotic prescribing, with the primary outcomes including total antibiotic prescriptions and prescriptions by WHO AWaRe group. We identified patient-specific factors associated with watch-group antibiotic prescribing through multivariable logistic regression analysis., Findings: Among 193,010 outpatient visits for ARIs observed in this study, 187,144 (97.0%) resulted in an antibiotic prescription, of which 172,976 (92.5%) were access-antibiotics, 10,765 (5.6%) were watch-antibiotics, 3366 (1.8%) were not-recommended antibiotics. No patients were treated with reserve-antibiotics. The proportion of watch-antibiotic prescription was highest amongst children under 5-years old (18.1%, compared to 9.5% for 5-17-years, 4.9% for 18-49-years, 4.3% for 50-64-years, and 3.7% for 65-and-above-years). In multivariable logistic regression, children, district, ARI-type, comobid chronic respiratory illness, and follow-up visit were associated with higher likelihood of prescribing watch-group antibiotics., Interpretation: The alarmingly high proportion of antibiotic prescriptions for ARIs in primary care, and the frequent use of watch-antibiotics for children, heighten concerns around antibiotic overuse at the community level. Antimicrobial stewardship interventions and policy attention are needed in primary care settings to tackle the growing threat of antibiotic resistance., Funding: This work was supported through Australian government and UK aid from the UK government funding to FIND (Foundation for Innovative New Diagnostics) grant number FO17-0015, in addition to a Wellcome Trust grant (213920/Z/18/Z), and an Oxford University Clinical Research Unit internal grant from the Wellcome Trust Africa Asia Programme core grant in Vietnam (106680/Z/14/Z)., Competing Interests: The authors declared no conflicts of interest., (Crown Copyright © 2022 Published by Elsevier Ltd.)

Efficient resource allocation is essential for effective pandemic response. We measured host biomarkers in 420 patients presenting with moderate coronavirus disease 2019 and found that different biomarkers predict distinct clinical outcomes. Interleukin (IL)-1ra, IL-6, IL-10, and IL-8 exhibit dose-response relationships with subsequent disease progression and could potentially be useful for multiple use-cases., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: We aimed to determine the cost-effectiveness of supplementing standard care with pulse oximetry among children <5 years with acute respiratory infection (ARI) presenting to 32 primary care units in a rural district (total population 241,436) of Chiang Rai province, Thailand, and to assess the economic effects of extending pulse oximetry to older patients with ARI in this setting., Methods: We performed a model-based cost-effectiveness analysis from a health systems perspective. Decision trees were constructed for three patient categories (children <5 years, children 5-14 years, and adults), with a 1-year time horizon. Model parameters were based on data from 49,958 patients included in a review of acute infection management in the 32 primary care units, published studies, and procurement price lists. Parameters were varied in deterministic sensitivity analyses. Costs were expressed in 2021 US dollars with a willingness-to-pay threshold per DALY averted of $8624., Results: The annual direct cost of pulse oximetry, associated staff, training, and monitoring was $24,243. It reduced deaths from severe lower respiratory tract infections in children <5 years by 0.19 per 100,000 patients annually. In our population of 14,075 children <5 years, this was equivalent to 2.0 DALYs averted per year. When downstream costs such as those related to hospitalisation and inappropriate antibiotic prescription were considered, pulse oximetry dominated standard care, saving $12,757 annually. This intervention yielded smaller mortality gains in older patients but resulted in further cost savings, primarily by reducing inappropriate antibiotic prescriptions in these age groups. The dominance of the intervention was also demonstrated in all sensitivity analyses., Conclusions: Pulse oximetry is a life-saving, cost-effective adjunct in ARI primary care management in rural northern Thailand. This finding is likely to be generalisable to neighbouring countries with similar disease epidemiology and health systems., (© 2022 The Authors Tropical Medicine & International Health Published by John Wiley & Sons Ltd.)

Background: In locations where few people have received coronavirus disease 2019 (COVID-19) vaccines, health systems remain vulnerable to surges in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Tools to identify patients suitable for community-based management are urgently needed., Methods: We prospectively recruited adults presenting to 2 hospitals in India with moderate symptoms of laboratory-confirmed COVID-19 to develop and validate a clinical prediction model to rule out progression to supplemental oxygen requirement. The primary outcome was defined as any of the following: SpO2 < 94%; respiratory rate > 30 BPM; SpO2/FiO2 < 400; or death. We specified a priori that each model would contain three clinical parameters (age, sex, and SpO2) and 1 of 7 shortlisted biochemical biomarkers measurable using commercially available rapid tests (C-reactive protein [CRP], D-dimer, interleukin 6 [IL-6], neutrophil-to-lymphocyte ratio [NLR], procalcitonin [PCT], soluble triggering receptor expressed on myeloid cell-1 [sTREM-1], or soluble urokinase plasminogen activator receptor [suPAR]), to ensure the models would be suitable for resource-limited settings. We evaluated discrimination, calibration, and clinical utility of the models in a held-out temporal external validation cohort., Results: In total, 426 participants were recruited, of whom 89 (21.0%) met the primary outcome; 257 participants comprised the development cohort, and 166 comprised the validation cohort. The 3 models containing NLR, suPAR, or IL-6 demonstrated promising discrimination (c-statistics: 0.72-0.74) and calibration (calibration slopes: 1.01-1.05) in the validation cohort and provided greater utility than a model containing the clinical parameters alone., Conclusions: We present 3 clinical prediction models that could help clinicians identify patients with moderate COVID-19 suitable for community-based management. The models are readily implementable and of particular relevance for locations with limited resources., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.)

Introduction. Rapid diagnostic tests (RDTs) that can facilitate the diagnosis of a panel of tropical infectious diseases are critically needed. DPP® Fever Panel II Asia is a multiplex lateral flow immunoassay comprising antigen and IgM panels for the diagnosis of pathogens that commonly cause febrile illness in Southeast Asia. Hypothesis/Gap Statement. Accuracy of DPP® Fever Panel II Asia has not been evaluated in clinical studies. Aim. To evaluate the sensitivity and specificity of DPP® Fever Panel II Asia for malaria, dengue and melioidosis. Methodology. We conducted a cohort-based case-control study. Both cases and controls were derived from a prospective observational study of patients presenting with community-acquired infections and sepsis in northeast Thailand (Ubon sepsis). We included 143 and 98 patients diagnosed with malaria or dengue based on a positive PCR assay and 177 patients with melioidosis based on a culture positive for Burkholderia pseudomallei . Controls included 200 patients who were blood culture-positive for Staphylococcus aureus , Escherichia coli or Klebsiella pneumoniae , and cases of the other diseases. Serum samples collected from all patients within 24 h of admission were stored and tested using the DPP® Fever Panel II Asia antigen and IgM multiplex assays. We selected cutoff values for each individual assay corresponding to a specificity of ≥95 %. When assessing diagnostic tests in combination, results were considered positive if either individual test was positive. Results. Within the DPP® Fever Panel II Asia antigen assay, a combination of pLDH and HRPII for malaria had a sensitivity of 91 % and a specificity of 97 %. The combination of dengue NS1 antigen and dengue antibody tests had a sensitivity of 61 % and a specificity of 91 %. The B. pseudomallei CPS antigen test had a sensitivity of 27 % and a specificity of 97 %. An odds ratio of 2.34 (95 % CI 1.16-4.72, P =0.02) was observed for the association between CPS positivity and mortality among melioidosis patients. Conclusion. The performance of the DPP® Fever Panel II Asia for diagnosis of malaria was high and that for dengue and melioidosis was relatively limited. For all three diseases, performance was comparable to that of other established RDTs. The potential operational advantages of a multiplex and quantitative point-of-care assay are substantial and warrant further investigation.

Host biomarker testing can be used as an adjunct to the clinical assessment of patients with infections and might be particularly impactful in resource-constrained settings. Research on the merits of this approach at peripheral levels of low- and middle-income country health systems is limited. In part, this is due to resource-intense requirements for sample collection, processing, and storage. We evaluated the stability of 16 endothelial and immune activation biomarkers implicated in the host response to infection stored in venous plasma and dried blood spot specimens at different temperatures for 6 months. We found that -80°C storage offered no clear advantage over -20°C for plasma aliquots, and most biomarkers studied could safely be stored as dried blood spots at refrigeration temperatures (4°C) for up to 3 months. These results identify more practical methods for host biomarker testing in resource-limited environments, which could help facilitate research in rural and remote environments.

In rural areas of South and Southeast Asia malaria is declining but febrile illnesses still account for substantial morbidity and mortality. Village health workers (VHWs) are often the first point of contact with the formal health system, and for patients with febrile illnesses they can provide early diagnosis and treatment of malaria. However, for the majority of febrile patients, VHWs lack the training, support and resources to provide further care. Consequently, treatable bacterial illnesses are missed, antibiotics are overused and poorly targeted, and patient attendance wanes along with declining malaria. This Open Letter announces the start of a new initiative, the Rural Febrile Illness (RFI) project, the first in a series of projects to be implemented as part of the South and Southeast Asian Community-based Trials Network (SEACTN) research programme. This multi-country, multi-site project will run in Bangladesh, Cambodia, Lao PDR, Thailand, and Myanmar. It will define the epidemiological baseline of febrile illness in nine remote and underserved areas of Asia where malaria endemicity is declining and access to health services is limited. The RFI project aims to determine the incidence, causes and outcomes of febrile illness; understand the opportunities, barriers and appetite for adjustment of the role of VHWs to include management of non-malarial febrile illnesses; and establish a network of community healthcare providers and facilities capable of implementing interventions designed to triage, diagnose and treat patients presenting with febrile illnesses within these communities in the future., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Chandna A et al.)

Background: Typhoid and paratyphoid fever (enteric fever) is a common cause of non-specific febrile infection in adults and children presenting to health care facilities in low resource settings such as the South Asia.  A 7-day course of a single oral antimicrobial such as ciprofloxacin, cefixime, or azithromycin is commonly used for its treatment. Increasing antimicrobial resistance threatens the effectiveness of these treatment choices. We hypothesize that combined treatment with azithromycin (active mainly intracellularly) and cefixime (active mainly extracellularly) will be a better option for the treatment of clinically suspected and culture-confirmed typhoid fever in South Asia. Methods: This is a phase IV, international multi-center, multi-country, comparative participant-and observer-blind, 1:1 randomised clinical trial. Patients with suspected uncomplicated typhoid fever will be randomized to one of the two interventions: Arm A: azithromycin 20mg/kg/day oral dose once daily (maximum 1gm/day) and cefixime 20mg/kg/day oral dose in two divided doses (maximum 400mg bd) for 7 days, Arm B: azithromycin 20mg/kg/day oral dose once daily (max 1gm/day) for 7 days AND cefixime-matched placebo for 7 days. We will recruit 1500 patients across sites in Bangladesh, India, Nepal, and Pakistan. We will assess whether treatment outcomes are better with the combination after one week of treatment and at one- and three-months follow-up. Discussion: Combined treatment may limit the emergence of resistance if one of the components is active against resistant sub-populations not covered by the other antimicrobial activity. If the combined treatment is better than the single antimicrobial treatment, this will be an important result for patients across South Asia and other typhoid endemic areas. Clinicaltrials.gov registration: NCT04349826 (16/04/2020)., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Giri A et al.)

Background: Acute fever is a common presenting symptom in low/middle-income countries (LMICs) and is strongly associated with sepsis. Hypoxaemia predicts disease severity in such patients but is poorly detected by clinical examination. Therefore, including pulse oximetry in the assessment of acutely febrile patients may improve clinical outcomes in LMIC settings., Methods: We systematically reviewed studies of any design comparing one group where pulse oximetry was used and at least one group where it was not. The target population was patients of any age presenting with acute febrile illness or associated syndromes in LMICs. Studies were obtained from searching PubMed, EMBASE, CABI Global Health, Global Index Medicus, CINAHL, Cochrane CENTRAL, Web of Science and DARE. Further studies were identified through searches of non-governmental organisation websites, snowballing and input from a Technical Advisory Panel. Outcomes of interest were diagnosis, management and patient outcomes. Study quality was assessed using the Cochrane Risk of Bias 2 tool for Cluster Randomised Trials and Risk of Bias in Non-randomized Studies of Interventions tools, as appropriate., Results: Ten of 4898 studies were eligible for inclusion. Their small number and heterogeneity prevented formal meta-analysis. All studies were in children, eight only recruited patients with pneumonia, and nine were conducted in Africa or Australasia. Six were at serious risk of bias. There was moderately strong evidence for the utility of pulse oximetry in diagnosing pneumonia and identifying severe disease requiring hospital referral. Pulse oximetry used as part of a quality-assured facility-wide package of interventions may reduce pneumonia mortality, but studies assessing this endpoint were at serious risk of bias., Conclusions: Very few studies addressed this important question. In LMICs, pulse oximetry may assist clinicians in diagnosing and managing paediatric pneumonia, but for the greatest impact on patient outcomes should be implemented as part of a health systems approach. The evidence for these conclusions is not widely generalisable and is of poor quality., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Antimicrobial resistance (AMR) is a major threat to global health. Improving laboratory capacity for AMR detection is critically important for patient health outcomes and population level surveillance. We aimed to estimate the financial cost of setting up and running a microbiology laboratory for organism identification and antimicrobial susceptibility testing as part of an AMR surveillance programme. Financial costs for setting up and running a microbiology laboratory were estimated using a top-down approach based on resource and cost data obtained from three clinical laboratories in the Mahidol Oxford Tropical Medicine Research Unit network. Costs were calculated for twelve scenarios, considering three levels of automation, with equipment sourced from either of the two leading manufacturers, and at low and high specimen throughput. To inform the costs of detection of AMR in existing labs, the unit cost per specimen and per isolate were also calculated using a micro-costing approach. Establishing a laboratory with the capacity to process 10,000 specimens per year ranged from $254,000 to $660,000 while the cost for a laboratory processing 100,000 specimens ranged from $394,000 to $887,000. Excluding capital costs to set up the laboratory, the cost per specimen ranged from $22-31 (10,000 specimens) and $11-12 (100,000 specimens). The cost per isolate ranged from $215-304 (10,000 specimens) and $105-122 (100,000 specimens). This study provides a conservative estimate of the costs for setting up and running a microbiology laboratory for AMR surveillance from a healthcare provider perspective. In the absence of donor support, these costs may be prohibitive in many low- and middle- income country (LMIC) settings. With the increased focus on AMR detection and surveillance, the high laboratory costs highlight the need for more focus on developing cheaper and cost-effective equipment and reagents so that laboratories in LMICs have the potential to improve laboratory capacity and participate in AMR surveillance., Competing Interests: Competing interests We declare that we have no conflicts of interest.

C-reactive protein (CRP) is used to discriminate common bacterial and viral infections, but its utility in tropical settings remains unknown. We performed a meta-analysis of studies performed in Asia and Africa. First, mean CRP levels for specific tropical infections were calculated. Thereafter, individual patient data (IPD) from patients with non-malarial undifferentiated fever (NMUF) who were tested for viral and bacterial pathogens were analysed, calculating separate cut-off values and their performance in classifying viral or bacterial disease. Mean CRP levels of 7307 patients from 13 countries were dengue 12.0 mg/l (standard error [SE] 2.7), chikungunya 41.0 mg/l (SE 19.5), influenza 15.9 mg/l (SE 6.3), Crimean-Congo haemorrhagic fever 9.7 mg/l (SE 4.7), Salmonella 61.9 mg/l (SE 5.4), Rickettsia 61.3 mg/l (SE 8.8), Coxiella burnetii 98.7 mg/l (SE 44.0) and Leptospira infections 113.8 mg/l (SE 23.1). IPD analysis of 1059 NMUF patients ≥5 y of age showed CRP <10 mg/l had 52% sensitivity (95% confidence interval [CI] 48 to 56) and 95% specificity (95% CI 93 to 97) to detect viral infections. CRP >40 mg/l had 74% sensitivity (95% CI 70 to 77) and 84% specificity (95% CI 81 to 87) to identify bacterial infections. Compared with routine care, the relative risk for incorrect classification was 0.64 (95% CI 0.55 to 0.75) and the number needed to test for one extra correctly classified case was 8 (95% CI 6 to 12). A two cut-off value CRP test may help clinicians to discriminate viral and bacterial aetiologies of NMUF in tropical areas., (© World Health Organization, 2021. All rights reserved. The World Health Organization has granted the Publisher permission for the reproduction of this article.)

Substandard and falsified (SF) antimalarials have devastating consequences including increased morbidity, mortality and economic losses. Portable medicine quality screening devices are increasingly available, but whether their use for the detection of SF antimalarials is cost-effective is not known. We evaluated the cost-effectiveness of introducing such devices in post-market surveillance in pharmacies in Laos, conservatively focusing on their outcome in detecting SF artemisinin-based combination therapies (ACTs). We simulated the deployment of six portable screening devices: two handheld near-infrared [MicroPHAZIR RX, NIR-S-G1], two handheld Raman [Progeny, TruScan RM]; one portable mid-infrared [4500a FTIR] spectrometers, and single-use disposable paper analytical devices [PADs]. We considered two scenarios with high and low levels of SF ACTs. Different sampling strategies in which medicine inspectors would test 1, 2, or 3 sample(s) of each brand of ACT were evaluated. Costs of inspection including device procurement, inspector time, reagents, reference testing, and replacement with genuine ACTs were estimated. Outcomes were measured as disability adjusted life years (DALYs) and incremental cost-effectiveness ratios were estimated for each device compared with a baseline of visual inspections alone. In the scenario with high levels of SF ACTs, all devices were cost-effective with a 1-sample strategy. In the scenario of low levels of SF ACTs, only four devices (MicroPHAZIR RX, 4500a FTIR, NIR-S-G1, and PADs) were cost-effective with a 1-sample strategy. In the multi-way comparative analysis, in both scenarios the NIR-S-G1 testing 2 samples was the most cost-effective option. Routine inspection of ACT quality using portable screening devices is likely to be cost-effective in the Laos context. This work should encourage policy-makers or regulators to further investigate investment in portable screening devices to detect SF medicines and reduce their associated undesired health and economic burdens., Competing Interests: The authors have declared that no competing interests exist.

Céline Caillet and co-authors discuss a Collection on use of portable devices for the evaluation of medicine quality and legitimacy., Competing Interests: The authors have declared that no competing interests exist.

Background: In 2017, an estimated 14 million cases of Plasmodium vivax malaria were reported from Asia, Central and South America, and the Horn of Africa. The clinical burden of vivax malaria is largely driven by its ability to form dormant liver stages (hypnozoites) that can reactivate to cause recurrent episodes of malaria. Elimination of both the blood and liver stages of the parasites ("radical cure") is required to achieve a sustained clinical response and prevent ongoing transmission of the parasite. Novel treatment options and point-of-care diagnostics are now available to ensure that radical cure can be administered safely and effectively. We quantified the global economic cost of vivax malaria and estimated the potential cost benefit of a policy of radical cure after testing patients for glucose-6-phosphate dehydrogenase (G6PD) deficiency., Methods and Findings: Estimates of the healthcare provider and household costs due to vivax malaria were collated and combined with national case estimates for 44 endemic countries in 2017. These provider and household costs were compared with those that would be incurred under 2 scenarios for radical cure following G6PD screening: (1) complete adherence following daily supervised primaquine therapy and (2) unsupervised treatment with an assumed 40% effectiveness. A probabilistic sensitivity analysis generated credible intervals (CrIs) for the estimates. Globally, the annual cost of vivax malaria was US$359 million (95% CrI: US$222 to 563 million), attributable to 14.2 million cases of vivax malaria in 2017. From a societal perspective, adopting a policy of G6PD deficiency screening and supervision of primaquine to all eligible patients would prevent 6.1 million cases and reduce the global cost of vivax malaria to US$266 million (95% CrI: US$161 to 415 million), although healthcare provider costs would increase by US$39 million. If perfect adherence could be achieved with a single visit, then the global cost would fall further to US$225 million, equivalent to $135 million in cost savings from the baseline global costs. A policy of unsupervised primaquine reduced the cost to US$342 million (95% CrI: US$209 to 532 million) while preventing 2.1 million cases. Limitations of the study include partial availability of country-level cost data and parameter uncertainty for the proportion of patients prescribed primaquine, patient adherence to a full course of primaquine, and effectiveness of primaquine when unsupervised., Conclusions: Our modelling study highlights a substantial global economic burden of vivax malaria that could be reduced through investment in safe and effective radical cure achieved by routine screening for G6PD deficiency and supervision of treatment. Novel, low-cost interventions for improving adherence to primaquine to ensure effective radical cure and widespread access to screening for G6PD deficiency will be critical to achieving the timely global elimination of P. vivax., Competing Interests: The authors have declared that no competing interests exist.

Background: Mass drug administration (MDA) has received growing interest to accelerate the elimination of multi-drug resistant malaria in the Greater Mekong Subregion. Targeted MDA, sometimes referred to as focal MDA, is the practice of delivering MDA to high incidence subpopulations only, rather than the entire population. The potential effectiveness of delivering targeted MDA was demonstrated in a recent intervention in Kayin State, Myanmar. Policymakers and funders need to know what resources are required if MDA, targeted or otherwise, is to be included in elimination packages beyond existing malaria interventions. This study aims to estimate the programmatic cost and the unit cost of targeted MDA in Kayin State, Myanmar., Methods: We used financial data from a malaria elimination initiative, conducted in Kayin State, to estimate the programmatic costs of the targeted MDA component using a micro-costing approach. Three activities (community engagement, identification of villages for targeted MDA, and conducting mass treatment in target villages) were evaluated. We then estimated the programmatic costs of implementing targeted MDA to support P. falciparum malaria elimination in Kayin State. A costing tool was developed to aid future analyses., Results: The cost of delivering targeted MDA within an integrated malaria elimination initiative in eastern Kayin State was approximately US$ 910,000. The cost per person reached, distributed among those in targeted and non-targeted villages, for the MDA component was US$ 2.5., Conclusion: This cost analysis can assist policymakers in determining the resources required to clear malaria parasite reservoirs. The analysis demonstrated the value of using financial data from research activities to predict programmatic implementation costs of targeting MDA to different numbers of target villages.

In rural areas of South and Southeast Asia malaria is declining but febrile illnesses still account for substantial morbidity and mortality. Village health workers (VHWs) are often the first point of contact with the formal health system, and for patients with febrile illnesses they can provide early diagnosis and treatment of malaria. However, for the majority of febrile patients, VHWs lack the training, support and resources to provide further care. Consequently, treatable bacterial illnesses are missed, antibiotics are overused and poorly targeted, and patient attendance wanes along with declining malaria. This Open Letter announces the start of a new initiative, the Rural Febrile Illness (RFI) project, the first in a series of projects to be implemented as part of the South and Southeast Asian Community-based Trials Network (SEACTN) research programme. This multi-country, multi-site project will begin in Bangladesh, Cambodia, Lao PDR, and Myanmar and will define the epidemiological baseline of febrile illness in five remote and underserved areas of Asia where malaria endemicity is declining and access to health services is limited. The RFI project aims to determine the incidence, causes and outcomes of febrile illness; understand the opportunities, barriers and appetite for adjustment of the role of VHWs to include management of non-malarial febrile illnesses; and establish a network of community healthcare providers and facilities capable of implementing interventions designed to triage, diagnose and treat patients presenting with febrile illnesses within these communities in the future., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Chandna A et al.)

Despite estimates suggesting Leptospira spp. being endemic in Southeast Asia, evidence remains limited. Diagnostic accuracy evaluations based on Leptospira ELISA mainly rely on hospitalized and severe patients; therefore, studies measuring the pathogen burden may be inaccurate in the community. We evaluated the Panbio Leptospira ELISA IgM among 656 febrile outpatients attending primary care in Chiangrai, Thailand, and Hlaing Tha Yar, Yangon, Myanmar. ELISA demonstrated limited diagnostic accuracy for the detection of acute leptospiral infection using the manufacturer recommended cutoff, with a sensitivity of 71.4% and specificity of 36.4%, and an area under the receiver operator characteristic curve value of 0.65 (95% CI: 0.41-0.89), compared with our reference test, the PCR assay. ELISA also performed poorly as a screening tool for detecting recent exposure to Leptospira spp. compared with the "gold-standard" microscopic agglutination test, with a specificity of 42.7%. We conclude that the utility of the Leptospira IgM ELISA for both serodiagnosis and seroprevalence is limited in our setting.

Background: Rotavirus is a major cause of diarrhoea in children less than five years old in Thailand. Vaccination has been shown to be an effective intervention to prevent rotavirus infections but has yet to be enlisted in the national immunisation programme. This study aimed to assess the cost-utility of introducing rotavirus vaccines, taking all WHO-prequalified vaccines into consideration., Methods: A cost-utility analysis was performed using a transmission dynamic model to estimate, from a societal perspective, the costs and outcomes of four WHO-prequalified rotavirus vaccines: Rotarix®, RotaTeq®, ROTAVAC® and ROTASIIL®. The model was used to simulate the impact of introducing the vaccines among children aged < 1 year and compare this with no rotavirus vaccination. The vaccination programme was considered to be cost-effective if the incremental cost-effectiveness ratio was less than a threshold of USD 5,110 per QALY gained., Results: Overall, without the vaccine, the model predicted the average annual incidence of rotavirus to be 312,118 cases. With rotavirus vaccination at a coverage of more than 95%, the average number of rotavirus cases averted was estimated to be 144,299 per year. All rotavirus vaccines were cost-saving. ROTASIIL® was the most cost-saving option, followed by ROTAVAC®, Rotarix® and RotaTeq®, providing average cost-savings of USD 32, 31, 23 and 22 million per year, respectively, with 999 QALYs gained. All vaccines remained cost-saving with lower QALYs gained, even when ignoring indirect beneficial effects. The net saving to the healthcare system when implementing any one of these vaccines would be between USD 13 and 33 million per year., Conclusion: Rotavirus vaccines should be included in the national vaccination programme in Thailand. Implementing any one of these four WHO-prequalified vaccines would reduce government healthcare spending while yielding health benefits to the population., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: In rural and difficult-to-access settings, early and accurate recognition of febrile children at risk of progressing to serious illness could contribute to improved patient outcomes and better resource allocation. This study aims to develop a prognostic clinical prediction tool to assist community healthcare providers identify febrile children who might benefit from referral or admission for facility-based medical care., Methods and Analysis: This prospective observational study will recruit at least 4900 paediatric inpatients and outpatients under the age of 5 years presenting with an acute febrile illness to seven hospitals in six countries across Asia. A venous blood sample and nasopharyngeal swab is collected from each participant and detailed clinical data recorded at presentation, and each day for the first 48 hours of admission for inpatients. Multianalyte assays are performed at reference laboratories to measure a panel of host biomarkers, as well as targeted aetiological investigations for common bacterial and viral pathogens. Clinical outcome is ascertained on day 2 and day 28.Presenting syndromes, clinical outcomes and aetiology of acute febrile illness will be described and compared across sites. Following the latest guidance in prediction model building, a prognostic clinical prediction model, combining simple clinical features and measurements of host biomarkers, will be derived and geographically externally validated. The performance of the model will be evaluated in specific presenting clinical syndromes and fever aetiologies., Ethics and Dissemination: The study has received approval from all relevant international, national and institutional ethics committees. Written informed consent is provided by the caretaker of all participants. Results will be shared with local and national stakeholders, and disseminated via peer-reviewed open-access journals and scientific meetings., Trial Registration Number: NCT04285021., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Most antibiotic prescribing occurs in primary care. Even within the same health facility, there may be differences between prescribers in their tendency to prescribe antibiotics, which may be masked by summary data. We aimed to quantify prescriber variability in antibiotic prescription to patients with acute fever in primary care clinics in Myanmar., Methods: We conducted a secondary analysis of prescribing data from 1090 patient consultations with 40 prescribing doctors from a trial investigating the effect of point-of-care C-reactive protein (CRP) tests on antibiotic prescription for acute fever. We used multilevel logistic regression models to assess inter-prescriber variability in the decision to prescribe antibiotics., Results: The median odds ratio (MOR) in the unadjusted model was 1.82 (95% CI: 1.47-2.56) indicating that when two prescribers from this population are randomly selected then in half of these pairs the odds of prescription will be greater than 1.82-fold higher in one prescriber than the other. The estimated variability from this sample of prescribers corresponds to a population of prescribers where the top 25% of prescribers will prescribe antibiotics to over 41% of patients while the bottom 25% will prescribe antibiotics to less than 23% of patients. Inter-prescriber variation in antibiotic prescribing remained after adjustment for patient characteristics and CRP information ( P  <   0.001)., Conclusions: Despite sharing the same management guidelines, there was substantial inter-prescriber variation in antibiotic prescription to patients with acute fever. This variation should be considered when designing trials and stewardship programmes aiming to reduce inappropriate antibiotic prescribing., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Introduction: Early identification of children at risk of severe febrile illness can optimise referral, admission and treatment decisions, particularly in resource-limited settings. We aimed to identify prognostic clinical and laboratory factors that predict progression to severe disease in febrile children presenting from the community., Methods: We systematically reviewed publications retrieved from MEDLINE, Web of Science and Embase between 31 May 1999 and 30 April 2020, supplemented by hand search of reference lists and consultation with an expert Technical Advisory Panel. Studies evaluating prognostic factors or clinical prediction models in children presenting from the community with febrile illnesses were eligible. The primary outcome was any objective measure of disease severity ascertained within 30 days of enrolment. We calculated unadjusted likelihood ratios (LRs) for comparison of prognostic factors, and compared clinical prediction models using the area under the receiver operating characteristic curves (AUROCs). Risk of bias and applicability of studies were assessed using the Prediction Model Risk of Bias Assessment Tool and the Quality In Prognosis Studies tool., Results: Of 5949 articles identified, 18 studies evaluating 200 prognostic factors and 25 clinical prediction models in 24 530 children were included. Heterogeneity between studies precluded formal meta-analysis. Malnutrition (positive LR range 1.56-11.13), hypoxia (2.10-8.11), altered consciousness (1.24-14.02), and markers of acidosis (1.36-7.71) and poor peripheral perfusion (1.78-17.38) were the most common predictors of severe disease. Clinical prediction model performance varied widely (AUROC range 0.49-0.97). Concerns regarding applicability were identified and most studies were at high risk of bias., Conclusions: Few studies address this important public health question. We identified prognostic factors from a wide range of geographic contexts that can help clinicians assess febrile children at risk of progressing to severe disease. Multicentre studies that include outpatients are required to explore generalisability and develop data-driven tools to support patient prioritisation and triage at the community level., Prospero Registration Number: CRD42019140542., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)